Structural insight into substrate and inhibitor discrimination by human P-glycoprotein

ABCB1, also known as P-glycoprotein, actively extrudes xenobiotic compounds across the plasma membrane of diverse cells, which contributes to cellular drug resistance and interferes with therapeutic drug delivery. We determined the 3.5-angstrom cryo-electron microscopy structure of substrate-bound human ABCB1 reconstituted in lipidic nanodiscs, revealing a single molecule of the chemotherapeutic compound paclitaxel (Taxol) bound in a central, occluded pocket. A second structure of inhibited, human-mouse chimeric ABCB1 revealed two molecules of zosuquidar occupying the same drug-binding pocket. Minor structural differences between substrate- and inhibitor-bound ABCB1 sites are amplified toward the…

• SN
  Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
• ET
  Eidgenössische Technische Hochschule Zürich
• O
  Oncosuisse
• NI
  National Institutes of Health

  Award: P20GM109091